Shimakawa Y.,London School of Hygiene and Tropical Medicine | Lemoine M.,Imperial College London | Njai H.F.,Medical Research Council MRC Unit | Bottomley C.,London School of Hygiene and Tropical Medicine | And 13 more authors.Gut | Year: 2015

Increasing urbanisation and affluence in developing countries is causing the rapid emergence of obesity. Obesity is a major cause of chronic diseases especially non-insulin dependent diabetes mellitus (NIDDM) and hypertension. This is leading to a dual burden of disease as these countries try to tackle high levels of both infections and chronic diseases of affluence. The nature of the links between obesity and chronic disease are not yet understood. ||This project focuses on the linkage between obesity and NIDDM. New lines of evidence have suggested that insulin resistance (the forerunner of diabetes) is caused by the expanded adipose tissue mass acting like a new endocrine organ, and secreting many bioactive messengers which can impair insulin action. Chronic (sub-clinical) inflammation also appears to be a strong predictor of the development of diabetes. It has been suggested that inflammatory cytokines (especially TNFa and IL-6) may mediate this effect. Our particular interest is in the possibility that both of these processes are influenced by the n6/n3 ratio in polyunsaturated dietary fatty acids (PUFAs). We have two studies in progress to test aspects of this theory in different urban settings of a developing country (Gambia - n3/n6 dietary intervention study) and an emergent country (Chile - nested-case control study of gestational diabetes).

Earlier work by the Nutrition Programme has described the poor micronutrient status of many rural Gambian women during pregnancy and lactation but the primary effect of micronutrient deficiencies on the development of the fetus is unclear. Previous maternal multimicronutrient supplementation trials elsewhere have tended to target women in established pregnancies with inconsistent results. However, data describing the impact of maternal micronutrient status in early feto-placental development are sparse. The placenta is pivotal in regulating fetal physiology and we hypothesise that improved maternal micronutrient status prior to conception and during early pregnancy will improve placental functional parameters, which are directly relevant to fetal development. A large, community-based randomised controlled trial is now underway throughout Kiang West, which aims to test this hypothesis on a sample of reproductive but non-pregnant and non-lactating women. The intervention being used is a daily dose of 15 vitamins and minerals, formulated by UNICEF and WHO as key components in effective maternal micronutrition and termed UNIMMAP. We expect to study 400 pregnancies from among this preconceptional sample population during the course of the trial.

Genes do not operate in a fixed manner. Their expression and function is modulated by the environment in which the organism finds itself at any time. Nutrition arguably represents the most important of these environmental exposures. It provides a variable mixture of molecular substrates many of which have pharmaco-chemical (as well as purely nutritional) influences. Research on nutrient-gene interactions is therefore a high priority. In instances where genes play a role in nutrient handling it is likely that certain combinations of genes and nutritional status could greatly modify the risk of disease through so-called effect concentration. ||This research is examining interactions between iron and two genes coding for iron-handling proteins (haptoglobin and NRAMP1) in influencing the susceptibility to, and clinical course of, the three infectious diseases ranking as the worlds greatest killers: TB, HIV and malaria. Since iron can have both positive and negative effects on the human host and the invading organism, and since iron is one of the most widely prescribed therapeutic agents, this research could have important implications for nutritional practice. ||A further component of this programme is investigating interactions between dietary energy and micronutrient intake during pregnancy and gene expression in fetal and postnatal life. This may be important because birthweight is a key prognostic indicator of a persons life-long health.

Protein-energy malnutrition remains a major health problem in underprivileged areas of the world with a spectrum of disease ranging from stunting and wasting to the severe clinical diseases of marasmus and kwashiorkor. Mild malnutrition leads to cognitive and developmental impairment, moderate malnutrition contributes strongly to general mortality, and severe malnutrition is frequently fatal. Most poor infants and children in developing countries suffer from persistent intestinal damage (tropical gastroenteropathy). The extent of this gastroenteropathy correlates well with growth failure, and seems to be key to the development of malnutrition. ||The primary focus of this research programme is to identify factors that initiate and perpetuate the gut damage, and to test possible interventions. Although malnourished children are classically considered to be immuno-suppressed, a key feature of tropical gastroenteropathy is an intense mucosal inflammation (with parallels to other inflammatory bowel diseases). ||Our research aims to understand this paradox through detailed studies of the cell-mediated and cytokine mechanisms regulating mucosal immunity. Since the problem seems to become self-perpetuating we are also testing interventions aimed at preventing the initiation of the damage. These are using very early high-dose vitamin A administration, probiotics, and long-chain polyunsaturated fatty acid supplementation. The ultimate aim of the research is to find improved methods of community prevention and hospital therapy for malnutrition.